Intra-articular corticoid injection induces circulating glucocorticoid bioactivity and systemic immune activation in juvenile idiopathic arthritis.

OBJECTIVE: To study the systemic effects of intra-articular (IA) glucocorticoid (GC) injections in juvenile idiopathic arthritis (JIA). METHODS: The study group comprised 21 JIA patients being treated with IA methylprednisolone [MP (n = 15) or MP plus triamcinolone hexacetonide (THA) (n = 6)] prescribed on clinical indications. The systemic effect of MP was assessed by measuring circulating glucocorticoid bioactivity (GBA) with a recombinant cell transactivation assay 7 and 24 h after the IA injections, and after 2 months. The systemic immunological responses were studied with a novel assay for testing patient serum-induced changes in the secretion of interferon (IFN)-γ and interleukin (IL)-5 from target cells. RESULTS: Administration of IA GC induced serum GBA (p = 0.001) and suppressed circulating cortisol levels (p = 0.002) 7 h after the injection. Serum withdrawn 24 h after the IA injection induced less IL-5 secretion from mitogen-activated target cells when compared with pre-treatment sera (p = 0.036). This decrease in target cell T helper (Th)2 response (IL-5) was MP dose related (r = -0.550, p = 0.018). High IL-5 secretion from target cells prior to the IA injections was associated with good clinical outcome at 2 months, seen as a low number of active (p = 0.044) and restricted joints (p = 0.049). CONCLUSION: IA GC injections have systemic effects that are reflected in the serum as an immediate elevation of GBA, a decrease of endogenous cortisol as well as a suppressive effect of patient serum on target cell IL-5 secretion. These systemic effects may play a role in the attenuation of disease activity.

Drug survival of the first and second course of anti-tumour necrosis factor agents in juvenile idiopathic arthritis.

OBJECTIVES: To evaluate drug survival (continuation rates on drug) of anti-tumour necrosis factor (TNF) agents in juvenile idiopathic arthritis (JIA) and predictors for treatment discontinuation. METHODS: A retrospective observational study on JIA patients taking etanercept (n = 105) or infliximab (n = 104) with at least one year follow-up. Kaplan-Meier curves and log-rank statistics were used to compare treatments and a proportional hazards model to assess risk factors for discontinuation. RESULTS: Etanercept versus infliximab treatment survival at 12 months was 83% versus 80%, at 24 months 68% versus 68%, at 36 months 64% versus 53%, at 48 months 61% versus 48% (p = 0.194), respectively. Reasons for discontinuing the first biological treatment were inefficacy (etanercept 28% vs infliximab 20%, p = 0.445), adverse events (7% vs 22%, p = 0.002) or inactive disease (10% vs 16%, p = 0.068). Women (hazard ratio (HR) 2.8, 95% CI 1.3 to 5.8), patients with systemic JIA (HR 7.8, 95% CI 1.7 to 34.9) or those taking infliximab (HR 2.0, 95% CI 1.2 to 3.3) were at higher risk of treatment discontinuation. One-third of the patients were switched to the second anti-TNF therapy, which was discontinued less frequently than the first. At 12 months treatment survival of etanercept was 60%, infliximab 58% and adalimumab 66% as the second-line anti-TNF therapy. CONCLUSIONS: Although infliximab was discontinued more often than etanercept because of adverse events, during a 48-month follow-up the overall treatment survival of etanercept and infliximab as the first biological agent in JIA was comparable. A switch from one anti-TNF agent to another appears a reasonable therapeutic option.

Empirical classification of children with JIA: a multidimensional approach to pain and well-being.

OBJECTIVE: To investigate the relationship between children's arthritis self-efficacy, trait-anxiety, depression, clinical state of the disease (pain, disability, number of somatic complaints and active joints) and age of the child. METHODS: Trait anxiety and depression of JIA patients were measured by standardized scales (STAIC and CDI). For assessing self-efficacy CASE-scale was used. Pain, CHAQ and active joint count were used as indicators of the disease severity. The K-means cluster procedure was used to classify 145 consecutively recruited patients aged 8 to 15, regarding age, trait-anxiety and depression. One-way multivariate analysis of variance (MANOVA) followed by separate ANOVA's was used for comparisons between the cluster groups. Associations between the cluster groups and the children's self-efficacy were then evaluated using multivariate analysis of variance (MANOVA). RESULTS: Four cluster groups were identified based on the degree of depression and trait-anxiety. Clinical disease-related parameters differed significantly in the cluster groups. Pain was not necessarily related to the severity of the disease or to the diagnosis (oligoarthritis, oligoextended and polyarthritis). A higher level of self-efficacy was related to lower levels of depression, trait anxiety and pain. CONCLUSION: In JIA, the clinical classification of disease activity and severity did not directly correspond with depression and trait-anxiety in children with JIA. Instead, these were regulated by a self-efficacy, which was associated with less pain and somatic complaints.

Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis.

OBJECTIVE: To evaluate the efficacy of adalimumab in juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: Retrospective observational study of 20 patients with JIA and chronic uveitis on adalimumab treatment. The ocular inflammation and improvement was assessed according to the Standardization of Uveitis Nomenclature criteria. RESULTS: At the initiation of adalimumab, the mean age of patients was 13.4 yrs and the mean duration of uveitis 8.7 yrs. Seventeen (85%) patients had polyarticular JIA and 19 (95%) had previously been on anti-TNF treatment. The mean duration of adalimumab therapy was 18.7 months. Of the 20 patients, 7 (35%) showed improved activity, 1 (5%) worsening activity and in 12 (60%) no change was observed in the activity of uveitis. Those with improved activity were younger and had shorter disease duration. The mean number of flares/yr decreased from 1.9 to 1.4 during adalimumab treatment. Serious adverse events or side-effects were not observed. Seven patients discontinued adalimumab during the follow-up: six because of inefficacy and one because of inactive uveitis. CONCLUSION: Adalimumab is a potential treatment option in JIA-associated uveitis, even in patients non-responsive to previous other anti-TNF therapy.

Improved factor structure for self-efficacy scales for children with JIA (CASE) and their parents (PASE).

OBJECTIVE: Self-efficacy is an important factor in helping children to cope with a chronic disease. In order to study it, we have to be able to develop a valid and reliable scale. We validated and further developed the CASE (Children's Arthritis Self-Efficacy) and PASE (Parent's Arthritis Self-Efficacy) scales in a Finnish juvenile idiopathic arthritis (JIA) patient and parent population. METHODS: One hundred and twenty JIA children and their parents completed the CASE and PASE assessments, respectively. Exploratory Factor Analysis (EFA) applying the Principal Axis Factoring method was conducted and extended by the use of Confirmatory Factor Analysis (CFA) to allow a theory-driven approach to determine the latent dimensions for both CASE and PASE scales. Construct validity was analysed by measuring the extent to which the CASE and PASE variables correlated with variables of children's and parents' depression scales and with the clinical parameters of the child in a way that can be explained theoretically. RESULTS: A two-factor solution in PASE corresponding to Barlow's factor solution did not fit the sample of Finnish parents. Instead, a three-factor model similar to that of the CASE scale fitted the data for the PASE scale with self-efficacy in somatic symptoms and psychological and social functioning as subscales. Construct validity was confirmed for both scales. CONCLUSION: The refined three-factor structure of the PASE scale and the slightly modified three-dimensional CASE scale were found to be robust scales enabling disease-specific analysis of somatic, psychological and social self-efficacy and comparisons between the patients and parents.

Effects of infliximab on cytokines, myeloperoxidase, and soluble adhesion molecules in patients with juvenile idiopathic arthritis.

OBJECTIVE: Infliximab is effective and well tolerated in the treatment of juvenile idiopathic arthritis (JIA). The aim of the present study was to measure circulating levels of inflammatory mediators in patients with JIA during treatment with infliximab. METHODS: Eight patients with active JIA refractory to standard treatments were treated with infliximab (3-4 mg/kg) at weeks 0, 2 and 6 and thereafter at approximately 6-week intervals up to 24 weeks. RESULTS: All patients (n = 8) responded to the treatment. By 6 weeks of treatment the number of active joints had reduced from 16+/-4 (mean+/-SEM) to 4+/-1 (p<0.01) and C-reactive protein (CRP) levels had fallen from 31+/-8 to 8+/-3 (p<0.001). Infliximab treatment also reduced the serum concentrations of interleukin-6 (IL-6), myeloperoxidase (MPO), and soluble adhesion molecules ICAM-1 (intercellular adhesion molecule-1), and E-selectin. Tumour necrosis factor-alpha (TNFalpha) levels tended to increase while the concentrations of endogenous TNF antagonists (sTNF-RI and sTNF-RII) reduced in most patients during treatment. CONCLUSIONS: Infliximab reduced serum levels of IL-6, MPO and soluble adhesion molecules in JIA patients, producing a good clinical response to the treatment.

Impact of anti-TNF treatment on growth in severe juvenile idiopathic arthritis.

OBJECTIVES: To evaluate the impact of anti-tumour necrosis factor (TNF) treatment on growth and to identify the predictors for the change in growth in severe juvenile idiopathic arthritis (JIA). METHODS: Data from 71 JIA patients (43 on etanercept, 28 on infliximab) were reviewed two years before and two years on the anti-TNF treatment. The patients had polyarticular disease course (48 polyarthritis, 19 extended oligoarthritis, two systemic arthritis, and two enthesitis related arthritis). At the initiation of the anti-TNF treatment, their mean age was 9.6 years and the mean duration of JIA, 5.7 years. RESULTS: In the patients with delayed growth before anti-TNF treatment (n = 53), the growth velocity, measured as the change in height standard deviation score, accelerated +0.45 (95% confidence interval, 0.33 to 0.56) (p<0.001) during the anti-TNF treatment. In the patients with normal or accelerated growth before anti-TNF treatment (n = 18), the change in growth velocity was +0.05 (0.07 to 0.16) (p = 0.39). At two years on anti-TNF treatment, the growth velocity between these two groups was similar. No difference was found between the patients treated with etanercept or infliximab. A decelerating growth rate before the anti-TNF treatment was the strongest predictor for the observed increase in the growth velocity. The change in the inflammatory activity remained a significant predictor of the growth velocity even after the decrease in glucocorticoid dose was taken into account. CONCLUSIONS: In the treatment of polyarticular JIA, the anti-TNF treatment not only suppresses inflammation but also restores growth velocity.

Biological treatment in rheumatic diseases: results from a longitudinal surveillance: adverse events.

The objective of this study was to assess the long-term safety and tolerability of biologicals in a clinical setting. Data on adverse events (AEs) have been collected over a 5-year period by means of detailed reports sent in to the National Register of Biological Treatment in Finland (ROB-FIN) and validated by information collected by the National Agency for Medicines. Three hundred and eight reports on AEs were filed, concerning a total of 248 patients; this corresponds to 17% of all patients in the ROB-FIN register who started biological treatments. Skin reactions and infections comprised 35 and 28% of the AEs, respectively. Some cases of tuberculosis and other infections, heart failure and demyelinating conditions were seen. Our work demonstrates no unexpected AEs in a Finnish patient cohort consisting of rheumatoid arthritis and spondylarthropathy patients, although many of them were treated with combination treatments in common use in Finland. Biological treatment appears safe in the hands of the Finnish rheumatologists.

Classic disease modifying anti-rheumatic drugs (DMARDs) in combination with infliximab. The Finnish experience.

To assess the performance of infliximab in a clinical setting, 364 rheumatoid arthritis (RA) patients from the National Register of Biological Treatment in Finland (ROB-FIN) were analysed. Corticosteroid usage and dose diminished (p<0.05 and 0.001, respectively) in patients on infliximab, of whom 51% also used one, 28% two and 16% three other concomitant DMARDs. A 34% of the RA patients used methotrexate+/-corticosteroids without any other DMARD. Methotrexate was most frequently used with sulphasalazine and/or hydroxychloroquine. Non-methotrexate patients most frequently used leflunomide or azathioprine combined with corticosteroids. The clinical effect of these combinations was similar to that of infliximab with methotrexate alone. The results indicate that infliximab can be used together with other DMARDs than methotrexate alone, quite according to the philosophy of the combination drug therapy, as the effectiveness is as good as or even slightly better than that of methotrexate and infliximab.

Intra-articular steroids in radiologically confirmed tarsal and hip synovitis of juvenile idiopathic arthritis.

OBJECTIVE: To estimate the value of MRI or US imaging in the diagnosis of synovitis and the response to local steroid therapy in tarsal and hip synovitis. METHODS: 32 patients with juvenile idiopathic arthritis (JIA), 19 of them with 22 tarsal and 13 of them with 20 hip synovitis, were followed up for 12 months after intra-articular corticosteroid treatment (IAST). MRI was taken from swollen ankles/feet to target the inflamed area before IAST. The synovitis in hip joints was assessed by both clinical and ultrasonographic examination. RESULTS: MRI showed that in the swollen tarsal area the inflammation was distributed widely in the joints and tendon sheaths. In 13/22 (59%) ankles/feet, synovitis was observed in multiple joint spaces. In 17/22 (77%) ankles/feet, tenosynovitis was present. In 32% of cases, the IAST induced clinical remission for up to 12 months. In hip synovitis, ultrasound supplemented clinical assessment. At 12 months after IAST a successful treatment response was seen in 10/20 (50%) hips. CONCLUSION: In unresponsive tarsal arthritis, the synovitic sites should be targeted by radiological imaging to improve the efficacy of corticosteroid injections. For pediatric rheumatologists, easy access to US is preferable to optimize the treatment of hip and tarsal synovitis in JIA.

Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study.

OBJECTIVE: To study infliximab and etanercept in the treatment of refractory juvenile idiopathic arthritis (JIA). METHODS: In a non-randomised, prospective, open label study, 24 patients (mean age 10.2 years, range 3.3-16.3) with polyarticular JIA were treated with either infliximab (n=14) or etanercept (n=10). The patients had had active polyarthritis for at least one year and standard treatment had failed. Anti-tumour necrosis factor (TNF) treatment was added to the current drug treatment. Infliximab (3-4 mg/kg) was given intravenously at weeks 0, 2, and 6, and thereafter at 4 to 8 week intervals. Etanercept (0.4 mg/kg) was given subcutaneously twice a week. Improvement of the patients was assessed at 3, 6, and 12 months according to established JIA response criteria. RESULTS: In intention to treat analyses, patients in both treatment groups improved significantly. ACR Paediatric 50 was achieved at 3, 6, and 12 months by 9/10 (90%), 8/9 (89%), and 8/9 (89%) patients with etanercept and by 8/12 (67%), 10/12 (83%), and 7/9 (78%) with infliximab, respectively. At 12 months, ACR Paediatric 75 was achieved by 67% of patients in both treatment groups. Five withdrawals due to adverse effects or lack of efficacy occurred in the infliximab group and one due to lack of compliance in the etanercept group. CONCLUSION: In this open label clinical study of active JIA, both infliximab and etanercept provided a significant rapid and sustained reduction in disease activity. Adequately powered randomised controlled trials are needed to elucidate the long term safety and efficacy of TNF modulators in the treatment of JIA.

Clinical relevance of the risk factors for coronary artery inflammation in Kawasaki disease.

The objective of this study was to determine predictive factors in children with Kawasaki disease (KD) with which we could distinguish the patients with KD who are either at very low risk or at very high risk for coronary artery inflammation (i.e., either patients who do not need intravenous immunoglobulin treatment or patients in whom more aggressive or even experimental therapies should be considered). Prospectively collected demographic, clinical, and laboratory data on 344 patients treated for KD were correlated with the patients' echocardiographic findings. The parameters studied were age, sex, duration of the fever, erythrocyte sedimentation rate, hemoglobin, white blood cell count, platelet count, and serum albumin. These were examined both in bivariable comparisons and in multiple logistic regression models. Low serum albumin, age <1 year, and the duration of the fever prior to treatment were risk factors for coronary arteritis. In the multivariable models, their combined predictive value for coronary lesions was poor, especially when identifying the patients at a low risk for coronary artery lesions (CALs). In fact, 44 of 98 patients with CALs were falsely classified to the low-risk group. Ten of 14 patients younger than 1 year of age, who also had low serum albumin (<30 g/L), had echocardiographically verified CALs, and 7 (50%) had a definite coronary artery aneurysm. We could not distinguish a group at such a low risk that these patients could be left untreated. Young patients with low albumin run a very high risk for CALs.

A three-stage clinical trial design for rare disorders.

Many clinical trials of uncommon diseases are underpowered because of the difficulty of recruiting adequate numbers of subjects. We propose a clinical trial design with improved statistical power compared to the traditional randomized trial for use in clinical trials of rare diseases. The three-stage clinical trial design consists of an initial randomized placebo-controlled stage, a randomized withdrawal stage for subjects who responded, and a third randomized stage for placebo non-responders who subsequently respond to treatment. Test level and power were assessed by computer-intensive exact calculations. The three-stage clinical trial design was found to be consistently superior to the traditional randomized trial design in all cases examined, with sample sizes typically reduced by 20 per cent to 30 per cent while maintaining comparable power. When a treatment clearly superior to placebo was considered, our design reached a power of 75 per cent with a sample of 21 patients compared with the 52 needed to attain this power when only a randomized controlled trial was used. In situations where patient numbers are limited, a three-stage clinical trial design may be a more powerful design than the traditional randomized trial for detecting clinical benefits.

The Finnish version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Finnish language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Finnish CHAQ-CHQ were validated with 3 forward and 1 backward translations. A total of 161 subjects were enrolled: 89 patients with JIA (9% systemic onset, 44% polyarticular onset, 26% extended oligoarticular subtype, and 21% persistent oligoarticular subtype) and 72 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Finnish version of the CHAQ-CHQ is a reliable and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Otitis media as a sign of Wegener's granulomatosis in childhood.

Wegener's granulomatosis (WG) is a rare disease among paediatric patients. Chronic otitis media with or without facial nerve dysfunction is a known manifestation of the disease among adults. A case of a 15-year-old boy with WG, whose initial symptoms were acute otitis media and facial nerve paralysis, is presented. The otorhinolaryngological manifestations, as well as diagnostic and current treatment modalities in paediatric patients with WG, are discussed.